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BIOL/CHEM 3361 Biochemistry I (and BIOL 6352) Spring 2014 Due:, March 3 at 5:00 pm in FO 3.602 (No late Problem Sets will be accepted.) (To void last...

1. a. An alpha helix of 20-25 amino acids is needed to span the plasma membrane of cells. Based on the dimensions of an alpha-helix, calculate the range in width of the membrane?
b. How many amino acids would be needed in an antiparallel beta strand to span the membrane?
c. The maltose transporter maltoporin (Mr 49,913) spans the outer membrane of E. coli.
It is comprised of 18 successive antiparallel β-strands arranged like the staves of a barrel to create a channel through the membrane. Beta-turns connect the strands on the periplasmic side of the membrane; loops connect the strands on the outer side. The N- and C-termini coincide with the ends of β-strands and are both on the periplasmic side. Calculate the average number of residues per outside loop?
d. Given that the distance between Cα’s of neighboring β-strands is 0.5 nm, what are the circumference and diameter of the β-barrel formed by the polypeptide backbone? Of course much of the interior of the barrel is occupied by side chains that narrow the channel and specify passage of only maltose and maltodextrins.
e. Given that the width and thickness of maltose are about 0.5 nm, what percent of the diameter would the channel for maltose transport need to occupy?

1 BIOL/CHEM 3361 Biochemistry I Due: Mon., March 3 at 5:00 pm in FO 3.602 (and BIOL 6352) ( No late Problem Sets will be accepted.) Spring 2014 (To void last minute difficulties, you may turn them in early -- at lecture or at FO 3.602 during departmental office hours.) PROBLEM SET 2 For full credit, all steps to the solutions of the following problems must be shown. You may work together on the problems, but you may not copy or plagiarize. Your answers must show your own math steps and be in your own words. 1. a. An alpha helix of 20-25 amino acids is needed to span the plasma membrane of cells. Based on the dimensions of an alpha-helix, calculate the range in width of the membrane? b. How many amino acids would be needed in an antiparallel beta strand to span the membrane? c. The maltose transporter maltoporin (Mr 49,913) spans the outer membrane of E. coli . It is comprised of 18 successive antiparallel β-strands arranged like the staves of a barrel to create a channel through the membrane. Beta-turns connect the strands on the periplasmic side of the membrane; loops connect the strands on the outer side. The N- and C-termini coincide with the ends of β-strands and are both on the periplasmic side. Calculate the average number of residues per outside loop? d. Given that the distance between Cα’s of neighboring β-strands is 0.5 nm, what are the circumference and diameter of the β-barrel formed by the polypeptide backbone? Of course much of the interior of the barrel is occupied by side chains that narrow the channel and specify passage of only maltose and maltodextrins. e. Given that the width and thickness of maltose are about 0.5 nm, what percent of the diameter would the channel for maltose transport need to occupy? 2. For Michaelis-Menten phosphatase X with a Ks for substrate binding of 0.85 x 10 -8 M, half maximal velocity is achieved with a substrate concentration of 0.35 μM. a. What kind of kinetics does this enzyme follow: rapid equilibrium or just the general steady state? Justify your answer. b. How many times larger is the catalytic rate constant than the reverse rate constant for substrate binding, k -1 , by this phosphatase? c. How many times smaller is the catalytic rate constant than the rate constant for substrate binding, k 1 ? d. How many times Km must the substrate concentration be in order to achieve a velocity that is 90% of Vmax? e. If the [E] total is increased 5 times in a reaction while [S] is left constant, how much greater will the initial velocity be?
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2 3. S -Warfarin, aka. Coumadin, is used as a blood thinner to prevent blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease and as a pesticide to kill rodents. It works very differently than Plavix, another common blood thinner (see question 6). Vitamin K, which is used as a cofactor for γ-carboxylation of Glu, becomes oxidized during the reaction and must be reduced before being reused. Warfarin inhibits the epoxide reductase and possibly another reductase involved in the 2-step reduction process. Without carboxylation of critical blood clotting proteins, clotting is diminished. Correspondingly, vitamin K can be administered and an antidote to an overdose of warfarin. While Plavix must be metabolized by liver cytochrome P450 enzymes to be activated, warfarin is inactivated by P450 oxidation prior to excretion. The following data represents a kinetic analysis of this oxidation and its inhibition by the stereoisomer R -warfarin and by sulfaphenazole. Use the above data and Excel or similar program to make a diagnostic Lineweaver-Burk plot, with trendline equations displayed on the plot, to answer to following questions: a. What are Km, Vmax and k cat for the P540 enzyme? Assume 1 active site /P450. b. What type of inhibitor is R -warfarin? What type is sulfaphenazole? Justify your answers. . 4. Answer the following additional questions using the question 3 plot: a. What are the Ki’s for the two inhibitors? b. What is the catalytic efficiency of the P450 enzyme for hydroxylation S -warfarin? How does this compare to the most efficient enzymes? (Express any difference in terms of orders of magnitude.) c. Would treatment to reduce blood clotting with purified S -warfarin rather than the typical R,S -mixture be beneficial? Explain. 5. Ethanol (Mr 46) in the body is oxidized to acetaldehyde by liver alcohol dehydrogenase (LADH). Other alcohols are also oxidized by LADH. For example, methanol (Mr 32), which is mildly intoxicating, is oxidized by LADH to the quite toxic product formaldehyde. The toxic effects of ingesting methanol (a component of many commercial solvents) can be reduced by administering ethanol. The ethanol acts as a competitive inhibitor of the methanol by displacing it from LADH. This provides sufficient time for the methanol to be harmlessly excreted by the kidneys. If an individual has ingested 100 ml of methanol (a lethal dose), how much 100 proof whiskey (50% ethanol by volume) must be imbibed to reduce the activity of the LADH towards methanol to 5% of its original value? The adult human body contains ~40 liters of aqueous fluids throughout which ingested alcohols are rapidly and uniformly mixed. S -Warfarin 7-hydroxylation by human cytochrome P450 enzyme S -warfarin V o , pmol/min/nmol P450 μM No inhibitor + 200 μM R -warfarin + 5 μM sulfaphenazole 500 36.0 15.42 23.5 200 33.3 14.29 15.0 100 29.7 12.72 9.31 50.0 24.4 10.44 5.31 20.0 15.8 6.79 ND
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